Safety and Efficacy of Enoxaparin vs Unfractionated Heparin in Patients With Non–ST-Segment Elevation Acute Coronary Syndromes Who Receive Tirofiban and Aspirin: A Randomized Controlled Trial

• Published in: JAMA : the journal of the American Medical Association 2004-07, Vol.292 (1), p.55-64
• Main Authors: Blazing, Michael A, de Lemos, James A, White, Harvey D, Fox, Keith A. A, Verheugt, Freek W. A, Ardissino, Diego, DiBattiste, Peter M, Palmisano, Joanne, Bilheimer, David W, Snapinn, Steven M, Ramsey, Karen E, Gardner, Laura H, Hasselblad, Vic, Pfeffer, Marc A, Lewis, Eldrin F, Braunwald, Eugene, Califf, Robert M
• Format: Article
• Language: English
• Subjects: Aged; Angina Pectoris - drug therapy; Angina Pectoris - mortality; Aspirin - therapeutic use; Biological and medical sciences; Cardiology. Vascular system; Cardiovascular disease; Clinical outcomes; Coronary heart disease; Drugs; Enoxaparin - therapeutic use; Female; Fibrinolytic Agents - therapeutic use; General aspects; Heart; Hemorrhage - epidemiology; Heparin - therapeutic use; Humans; Male; Medical sciences; Medical treatment; Middle Aged; Myocardial Infarction - epidemiology; Platelet Aggregation Inhibitors - therapeutic use; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Treatment Outcome; Tyrosine - analogs & derivatives; Tyrosine - therapeutic use
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.292.1.55

CONTEXT Enoxaparin or the combination of glycoprotein IIb/IIIa inhibitor tirofiban with unfractionated heparin independently have shown superior efficacy over unfractionated heparin alone in patients with non–ST-elevation acute coronary syndromes (ACS). It is not clear if combining enoxaparin with glycoprotein IIb/IIIa inhibitors is as safe or as effective as the current standard combination of unfractionated heparin with glycoprotein IIb/IIIa inhibitors. OBJECTIVE To assess efficacy and safety of the combination of enoxaparin and tirofiban compared with unfractionated heparin and tirofiban in patients with non–ST-elevation ACS. DESIGN, SETTING, AND PARTICIPANTS A prospective, international, open-label, randomized, noninferiority trial of 1 mg/kg of enoxaparin every 12 hours (n = 2026) compared with weight-adjusted intravenous unfractionated heparin (n = 1961) in patients with non–ST-elevation ACS receiving tirofiban and aspirin. Phase A of the A to Z trial was conducted between December 1999 and May 2002. MAIN OUTCOME MEASURES Death, recurrent myocardial infarction, or refractory ischemia at 7 days in the intent-to-treat population with boundaries set for superiority and noninferiority. Safety based on measures of bleeding using the Thrombolysis in Myocardial Infarction (TIMI) classification system. RESULTS A total of 169 (8.4%) of 2018 patients randomized to enoxaparin experienced death, myocardial infarction, or refractory ischemia at 7 days compared with 184 (9.4%) of 1952 patients randomized to unfractionated heparin (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.71-1.08). This met the prespecified criterion for noninferiority. All components of the composite primary and secondary end points favored enoxaparin except death, which occurred in only 1% of patients (23 for enoxaparin and 17 for unfractionated heparin). Rates for any TIMI grade bleeding were low (3.0% for enoxaparin and 2.2% for unfractionated heparin; P = .13). Using a worst-case approach that combined 2 independent bleeding evaluations, use of enoxaparin was associated with 1 additional TIMI major bleeding episode for each 200 patients treated. CONCLUSIONS In patients receiving tirofiban and aspirin, enoxaparin is a suitable alternative to unfractionated heparin for treatment of non–ST-elevation ACS. The 12% relative and 1% absolute reductions in the primary end point in favor of enoxaparin met criterion for noninferiority and are consistent with prior trials performed without